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https://www.readbyqxmd.com/read/29352118/pi3k-mtor-inhibition-promotes-the-regression-of-experimental-vascular-malformations-driven-by-pik3ca-activating-mutations
#1
Laura di Blasio, Alberto Puliafito, Paolo Armando Gagliardi, Valentina Comunanza, Desiana Somale, Giulia Chiaverina, Federico Bussolino, Luca Primo
Somatic activating mutations within the PIK3CA gene have been recently detected in sporadic lymphatic and venous malformations, and in vascular malformations (VM) associated to overgrowth syndromes, such as CLOVES and Klippel-Trenaunay syndrome. Although VM are often limited to specific tissue areas and can be well treated, in extended or recurrent lesions novel therapeutic approaches are needed. We generated a mouse model of VM by local expression of PIK3CA-activating mutation in endothelial cells. PIK3CA-driven lesions are characterized by large areas of hemorrhage, hyperplastic vessels, infiltrates of inflammatory cells, and elevated endothelial cell density...
January 19, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29352106/cholesterol-binding-to-a-conserved-site-modulates-conformation-pharmacology-and-transport-kinetics-of-the-human-serotonin-transporter
#2
Louise Laursen, Kasper Severinsen, Kristina Birch Kristensen, Xavier Periole, Malene Overby, Heidi Kaastrup Müller, Birgit Schiøtt, Steffen Sinning
The serotonin transporter (SERT) is important for reuptake of the neurotransmitter serotonin from the synaptic cleft and is also the target of most antidepressants. It has previously been shown that cholesterol in the membrane bilayer affects the conformation of the serotonin transporter. Although recent crystal structures have identified several potential cholesterol binding sites it is unclear whether any of these potential cholesterol sites are occupieed by cholesterol and functionally relevant. In the present study we focus on the conserved Cholesterol Site 1 (CHOL1) located in a hydrophobic groove between TM1a, TM5 and TM7...
January 19, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29352087/subtype-specific-selection-for-resistance-to-fluoroquinolones-but-not-to-tetracyclines-occurs-in-campylobacter-jejuni-from-beef-cattle-in-confined-feeding-operations-in-southern-alberta-canada
#3
Andrew L Webb, L Brent Selinger, Eduardo N Taboada, G Douglas Inglis
Campylobacter jejuni was longitudinally isolated from beef cattle housed in four confined feeding operations (CFOs) in southern Alberta over 18 months. All of the cattle were administered a variety of antimicrobial agents (AMAs) non-therapeutically and metaphylactically during their time in the CFOs. In total, 7966 C. jejuni isolates were recovered from cattle. More animals were colonized by the bacterium after >60 days in the CFO (i.e. interim) compared to individuals upon entry at the CFO (i.e. arrival)...
January 19, 2018: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/29352080/functional-analysis-of-cancer-associated-dna-polymerase-%C3%AE%C2%B5-variants-in-saccharomyces-cerevisiae
#4
Stephanie R Barbari, Daniel P Kane, Elizabeth A Moore, Polina V Shcherbakova
DNA replication fidelity relies on base selectivity of the replicative DNA polymerases, exonucleolytic proofreading, and post-replicative DNA mismatch repair (MMR). Ultramutated human cancers without MMR defects carry alterations in the exonuclease domain of DNA polymerase ε (Polε). They have been hypothesized to result from defective proofreading. However, modeling in yeast of the most common variant, Polε-P286R, produced an unexpectedly strong mutator effect that exceeded the effect of proofreading deficiency by two orders of magnitude and indicated the involvement of other infidelity factors...
January 19, 2018: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29351740/population-size-may-shape-the-accumulation-of-functional-mutations-following-domestication
#5
Jianhai Chen, Pan Ni, Xinyun Li, Jianlin Han, Ivan Jakovlić, Chengjun Zhang, Shuhong Zhao
BACKGROUND: Population genetics theory predicts an important role of differences in the effective population size (N e ) among species on shaping the accumulation of functional mutations by regulating the selection efficiency. However, this correlation has never been tested in domesticated animals. RESULTS: Here, we synthesized 62 whole genome data in eight domesticated species (cat, dog, pig, goat, sheep, chicken, cattle and horse) and compared domesticates with their wild (or ancient) relatives...
January 19, 2018: BMC Evolutionary Biology
https://www.readbyqxmd.com/read/29351395/macrophage-colony-stimulating-factor-increases-hepatic-macrophage-content-liver-growth-and-lipid-accumulation-in-neonatal-rats
#6
Clare Pridans, Kristin A Sauter, Katharine M Irvine, Gemma M Davis, Lucas Lefevre, Anna Raper, Rocio Rojo, Ajit J Nirmal, Philippa Beard, Michael Cheeseman, David A Hume
Signaling via the colony stimulating factor 1 receptor (CSF1R) controls the survival, differentiation and proliferation of macrophages. Mutations in CSF1, or CSF1R in mice and rats have pleiotropic effects on postnatal somatic growth. We tested the possible application of CSF1-Fc as a therapy for low birth weight (LBW) at term, using a model based upon maternal dexamethasone treatment in rats. Neonatal CSF1-Fc treatment did not alter somatic growth, and did not increase the blood monocyte count. Instead, there was a substantial increase in the size of liver in both control and LBW rats, and the treatment greatly exacerbated the lipid droplet accumulation seen in the dexamethasone LBW model...
December 21, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/29351318/invasive-bacterial-disease-trends-and-characterization-of-group-b-streptococcal-isolates-among-young-infants-in-southern-mozambique-2001-2015
#7
Betuel Sigaúque, Miwako Kobayashi, Delfino Vubil, Ariel Nhacolo, Alberto Chaúque, Benild Moaine, Sérgio Massora, Inácio Mandomando, Tacilta Nhampossa, Quique Bassat, Fabiana Pimenta, Clara Menéndez, Maria da Gloria Carvalho, Eusebio Macete, Stephanie J Schrag
BACKGROUND: Maternal group B streptococcal (GBS) vaccines under development hold promise to prevent GBS disease in young infants. Sub-Saharan Africa has the highest estimated disease burden, although data on incidence and circulating strains are limited. We described invasive bacterial disease (IBD) trends among infants <90 days in rural Mozambique during 2001-2015, with a focus on GBS epidemiology and strain characteristics. METHODS: Community-level birth and mortality data were obtained from Manhiça's demographic surveillance system...
2018: PloS One
https://www.readbyqxmd.com/read/29351098/prognostic-factors-change-over-time-after-hepatectomy-for-colorectal-liver-metastases-a-multi-institutional-international-analysis-of-1099-patients
#8
Georgios Antonios Margonis, Stefan Buettner, Nikolaos Andreatos, Doris Wagner, Kazunari Sasaki, Carlotta Barbon, Andrea Beer, Carsten Kamphues, Inger Marie Løes, Jin He, Timothy M Pawlik, Klaus Kaczirek, George Poultsides, Per Eystein Lønning, John L Cameron, Hans Joerg Mischinger, Federico N Aucejo, Martin E Kreis, Christopher L Wolfgang, Matthew J Weiss
OBJECTIVE: To evaluate the changing impact of genetic and clinicopathologic factors on conditional overall survival (CS) over time in patients with resectable colorectal liver metastasis. BACKGROUND: CS estimates account for the changing likelihood of survival over time and may reveal the changing impact of prognostic factors as time accrues from the date of surgery. METHODS: CS analysis was performed in 1099 patients of an international, multi-institutional cohort...
January 18, 2018: Annals of Surgery
https://www.readbyqxmd.com/read/29350774/hepatitis-b-virus-surface-gene-pre-s2-mutant-as-a-high-risk-serum-marker-for-hepatoma-recurrence-after-curative-hepatic-resection
#9
Chia-Jui Yen, Yu-Lin Ai, Hung-Wen Tsai, Shih-Huang Chan, Chia-Sheng Yen, Kuang-Hsiung Cheng, Yun-Ping Lee, Chia-Wei Kao, Yu-Chun Wang, Yi-Lin Chen, Cheng-Han Lin, Tsunglin Liu, Huey-Pin Tsai, Jen-Ren Wang, Ih-Jen Su, Wenya Huang
Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC). The pre-S2 mutant large HBV surface antigen (LHBS) is highly associated with HCC. This study aimed to analyze the expression of the large form of surface protein in tumors and to evaluate the LHBS with mutations within the pre-S2 region as a high-risk recurrence marker in HCC patients after curative hepatic resection. By the analyses of immunohistochemical staining (N = 12) and Western Blotting (N = 22), the HBV surface protein, which is mainly comprised of the major form of HBS, was greatly diminished in the tumors...
January 19, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29350407/recent-progress-in-the-antiviral-activity-and-mechanism-study-of-pentacyclic-triterpenoids-and-their-derivatives
#10
REVIEW
Sulong Xiao, Zhenyu Tian, Yufei Wang, Longlong Si, Lihe Zhang, Demin Zhou
Viral infections cause many serious human diseases with high mortality rates. New drug-resistant strains are continually emerging due to the high viral mutation rate, which makes it necessary to develop new antiviral agents. Compounds of plant origin are particularly interesting. The pentacyclic triterpenoids (PTs) are a diverse class of natural products from plants composed of three terpene units. They exhibit antitumor, anti-inflammatory, and antiviral activities. Oleanolic, betulinic, and ursolic acids are representative PTs widely present in nature with a broad antiviral spectrum...
January 19, 2018: Medicinal Research Reviews
https://www.readbyqxmd.com/read/29350283/epigenetic-regulation-of-neuroblastoma-development
#11
REVIEW
Durinck Kaat, Speleman Frank
In recent years, technological advances have enabled a detailed landscaping of the epigenome and the mechanisms of epigenetic regulation that drive normal cell function, development and cancer. Rather than merely a structural entity to support genome compaction, we now look at chromatin as a very dynamic and essential constellation that is actively participating in the tight orchestration of transcriptional regulation as well as DNA replication and repair. The unique feature of chromatin flexibility enabling fast switches towards more or less restricted epigenetic cellular states is, not surprisingly, intimately connected to cancer development and treatment resistance, and the central role of epigenetic alterations in cancer is illustrated by the finding that up to 50% of all mutations across cancer entities affect proteins controlling the chromatin status...
January 19, 2018: Cell and Tissue Research
https://www.readbyqxmd.com/read/29350207/association-between-cyp2c19-and-abcb1-polymorphisms-and-clopidogrel-resistance-in-clopidogrel-treated-chinese-patients
#12
Zhong Ling Zhuo, Hai Peng Xian, Yan Long, Chang Liu, Yuan Yuan Sun, Yin Ting Ma, Hua Gao, Jing Zhong Zhao, Xiao Tao Zhao
OBJECTIVE: To investigate the association between CYP2C19 and ABCB1 polymorphisms and clopidogrel resistance (CR) in patients with cardiovascular disease in Beijing district. METHODS: In total, 325 patients were enrolled in the study, including 101 experimental group patients and 224 control group patients. The experimental group was divided into CR group (n=30) and non-CR group (n=71) according to the adenosine diphosphate (ADP)-induced platelet inhibition rate in thromboelastography (TEG) (ADP-induced platelet inhibition rate of <30% was defined as CR and rate of 30%-100% was defined as non-CR)...
January 19, 2018: Anatolian Journal of Cardiology
https://www.readbyqxmd.com/read/29349657/association-between-tbk1-mutations-and-risk-of-amyotrophic-lateral-sclerosis-frontotemporal-dementia-spectrum-a-meta-analysis
#13
Rongrong Cui, Miao Tuo, Pengfei Li, Chang Zhou
Recently, mutations in TBK1 (TANK-binding kinase 1) have been reported to be a cause of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) spectrum, but the relationship between them remains unclear owing to the small sample size and low mutation rate. Therefore, we performed a two-stage meta-analysis to investigate the frequency of TBK1 mutations in ALS/FTD patients and the association between the mutations and risk of ALS/FTD spectrum. In the first stage, 12 studies involving 4173 ALS/FTD patients were included...
January 18, 2018: Neurological Sciences
https://www.readbyqxmd.com/read/29349600/beneficial-mutations-from-evolution-experiments-increase-rates-of-growth-and-fermentation
#14
Aysha L Sezmis, Martino E Malerba, Dustin J Marshall, Michael J McDonald
A major goal of evolutionary biology is to understand how beneficial mutations translate into increased fitness. Here, we study beneficial mutations that arise in experimental populations of yeast evolved in glucose-rich media. We find that fitness increases are caused by enhanced maximum growth rate (R) that come at the cost of reduced yield (K). We show that for some of these mutants, high R coincides with higher rates of ethanol secretion, suggesting that higher growth rates are due to an increased preference to utilize glucose through the fermentation pathway, instead of respiration...
January 18, 2018: Journal of Molecular Evolution
https://www.readbyqxmd.com/read/29349598/phase-ib-study-evaluating-safety-and-clinical-activity-of-the-anti-her3-antibody-lumretuzumab-combined-with-the-anti-her2-antibody-pertuzumab-and-paclitaxel-in-her3-positive-her2-low-metastatic-breast-cancer
#15
Andreas Schneeweiss, Tjoung-Won Park-Simon, Joan Albanell, Ulrik Lassen, Javier Cortés, Veronique Dieras, Marcus May, Christoph Schindler, Frederik Marmé, Juan Miguel Cejalvo, Maria Martinez-Garcia, Iria Gonzalez, Jose Lopez-Martin, Anja Welt, Christelle Levy, Florence Joly, Francesca Michielin, Wolfgang Jacob, Céline Adessi, Annie Moisan, Georgina Meneses-Lorente, Tomas Racek, Ian James, Maurizio Ceppi, Max Hasmann, Martin Weisser, Andrés Cervantes
Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m2 weekly in all cohorts)...
January 19, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29349042/an-optimized-targeted-next-generation-sequencing-approach-for-sensitive-detection-of-single-nucleotide-variants
#16
S Stasik, C Schuster, C Ortlepp, U Platzbecker, M Bornhäuser, J Schetelig, G Ehninger, G Folprecht, C Thiede
Monitoring of minimal residual disease (MRD) has become an important clinical aspect for early relapse detection during follow-up care after cancer treatment. Still, the sensitive detection of single base pair point mutations via Next-Generation Sequencing (NGS) is hampered mainly due to high substitution error rates. We evaluated the use of NGS for the detection of low-level variants on an Ion Torrent PGM system. As a model case we used the c.1849G > T (p.Val617Phe) mutation of the JAK2-gene. Several reaction parameters (e...
May 2018: Biomolecular Detection and Quantification
https://www.readbyqxmd.com/read/29348614/noise-induced-bistability-in-the-fate-of-cancer-phenotypic-quasispecies-a-bit-strings-approach
#17
Josep Sardanyés, Tomás Alarcón
Tumor cell populations are highly heterogeneous. Such heterogeneity, both at genotypic and phenotypic levels, is a key feature during tumorigenesis. How to investigate the impact of this heterogeneity in the dynamics of tumors cells becomes an important issue. Here we explore a stochastic model describing the competition dynamics between a pool of heterogeneous cancer cells with distinct phenotypes and healthy cells. This model is used to explore the role of demographic fluctuations on the transitions involving tumor clearance...
January 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29348607/evaluation-of-mitochondrial-bioenergetics-dynamics-endoplasmic-reticulum-mitochondria-crosstalk-and-reactive-oxygen-species-in-fibroblasts-from-patients-with-complex-i-deficiency
#18
Guilhian Leipnitz, Al-Walid Mohsen, Anuradha Karunanidhi, Bianca Seminotti, Vera Y Roginskaya, Desiree M Markantone, Mateus Grings, Stephanie J Mihalik, Peter Wipf, Bennett Van Houten, Jerry Vockley
Mitochondrial complex I (CI) deficiency is the most frequent cause of oxidative phosphorylation (OXPHOS) disorders in humans. In order to benchmark the effects of CI deficiency on mitochondrial bioenergetics and dynamics, respiratory chain (RC) and endoplasmic reticulum (ER)-mitochondria communication, and superoxide production, fibroblasts from patients with mutations in the ND6, NDUFV1 or ACAD9 genes were analyzed. Fatty acid metabolism, basal and maximal respiration, mitochondrial membrane potential, and ATP levels were decreased...
January 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29348585/a-surrogate-reporter-system-for-multiplexable-evaluation-of-crispr-cas9-in-targeted-mutagenesis
#19
Hongmin Zhang, Yuexin Zhou, Yinan Wang, Yige Zhao, Yeting Qiu, Xinyi Zhang, Di Yue, Zhuo Zhou, Wensheng Wei
Engineered nucleases in genome editing manifest diverse efficiencies at different targeted loci. There is therefore a constant need to evaluate the mutation rates at given loci. T7 endonuclease 1 (T7E1) and Surveyor mismatch cleavage assays are the most widely used methods, but they are labour and time consuming, especially when one must address multiple samples in parallel. Here, we report a surrogate system, called UDAR (Universal Donor As Reporter), to evaluate the efficiency of CRISPR/Cas9 in targeted mutagenesis...
January 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29348486/phase-i-dose-escalation-study-of-copanlisib-in-combination-with-gemcitabine-or-cisplatin-plus-gemcitabine-in-patients-with-advanced-cancer
#20
R D Kim, S R Alberts, C Peña, I Genvresse, A Ajavon-Hartmann, C Xia, A Kelly, J E Grilley-Olson
BACKGROUND: Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α/δ activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo...
January 18, 2018: British Journal of Cancer
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